SUMMARY Despite medical advances, multiple myeloma remains a fatal disease. The mechanisms underpinning how myeloma progresses in the local bone microenvironment and through which myeloma colonizes the skeleton to generate multiple painful osteolytic lesions needs to be addressed urgently. Matrix metalloproteinases (MMPs) are key regulators of tumor-bone interaction via the regulation of cytokine and growth factor bioavailability/activity. Emerging data from our group has identified that in human specimens of the disease, MMP-13 is highly expressed by both the myeloma cells and the cells of the bone microenvironment namely, bone building osteoblasts. In vivo analyses show that when MMP-13 is genetically ablated from the host compartment there is a significant increase in overall survival and a concomitant decrease in myeloma induced bone disease. We also have identified that myeloma derived exosomes can promote the skeletal colonization of myeloma and, are rich in MMP-13. Further, preliminary data with a novel highly selective MMP-13 inhibitor significantly limits myeloma growth in vitro and in vivo underscoring the role for MMP-13 activity in driving multiple myeloma. Based on these preliminary findings we hypothesize that MMP-13 contributes to multiple myeloma progression. We will test our hypothesis by; 1) Defining the role of tumor and osteoblast derived MMP-13 in multiple myeloma progression. We will use CRISPR/cDNA overexpression approaches to manipulate the levels of MMP-13 in myeloma cell lines while using specific Cre-recombinase driven promoters to eliminate MMP-13 expression by osteoblasts. We will then test whether the presence or absence of MMP-13 in one or both compartments contributes to myeloma growth and associated bone disease in two separate in vivo models (5TGM1 and U266). We will also explore MMP-13 mechanisms of action with preliminary work pointing to regulation of transforming growth factor? (TGF?) activity. 2) Determining the role of myeloma derived exosomes and specifically exosomal MMP-13 in the skeletal colonization of the disease. We will also examine whether exosomal MMP-13, can identify smoldering multiple myeloma patients (n=200) at high-risk of progression to active disease using proteomic techniques. 3) Identifying the efficacy of a selective MMP-13 inhibitor in limiting multiple myeloma viability using CD138 isolated myeloma cells obtained from newly diagnosed patients in a novel ex vivo high throughput platform and clinically relevant in vivo models of the disease. Based on the anticipated results, interrogating the role MMP-13 in multiple myeloma progression will reveal a number of novel insights thereby providing a strong rationale for the translation of selective MMP-13 inhibitors to the clinic that we predict would have limited off-target effects due to the restricted skeletal expression of MMP-13.